Matrix Degradation in Human Immunodeficiency Virus Type 1-Associated Tuberculosis and Tuberculosis Immune Reconstitution Inflammatory Syndrome: A Prospective Observational Study.

Background: Extensive immunopathology occurs in human immunodeficiency virus (HIV)/tuberculosis (TB) coinfection, but the underlying molecular mechanisms are not well-defined. Excessive matrix metalloproteinase (MMP) activity is emerging as a key process but has not been systematically studied in HIV-associated TB. Methods: We performed a cross-sectional study of matrix turnover in HIV type 1 (HIV-1)-infected and -uninfected TB patients and controls, and a prospective cohort study of HIV-1-infected TB patients at risk of TB immune reconstitution inflammatory syndrome (TB-IRIS), in Cape Town, South Africa. Sputum and plasma MMP concentrations were quantified by Luminex, plasma procollagen III N-terminal propeptide (PIIINP) by enzyme-linked immunosorbent assay, and urinary lipoarabinomannan (LAM) by Alere Determine TB LAM assay. Peripheral blood mononuclear cells from healthy donors were cultured with Mycobacterium tuberculosis and extracellular matrix in a 3D model of TB granuloma formation. Results: MMP activity differed between HIV-1-infected and -uninfected TB patients and corresponded with specific TB clinical phenotypes. HIV-1-infected TB patients had reduced pulmonary MMP concentrations, associated with reduced cavitation, but increased plasma PIIINP, compared to HIV-1-uninfected TB patients. Elevated extrapulmonary extracellular matrix turnover was associated with TB-IRIS, both before and during TB-IRIS onset. The predominant collagenase was MMP-8, which was likely neutrophil derived and M. tuberculosis-antigen driven. Mycobacterium tuberculosis-induced matrix degradation was suppressed by the MMP inhibitor doxycycline in vitro. Conclusions: MMP activity in TB differs by HIV-1 status and compartment, and releases matrix degradation products. Matrix turnover in HIV-1-infected patients is increased before and during TB-IRIS, informing novel diagnostic strategies. MMP inhibition is a potential host-directed therapy strategy for prevention and treatment of TB-IRIS

Invariant Natural Killer T cell dynamics in HIV-associated tuberculosis.

RATIONALE: Tuberculosis (TB) is the leading cause of mortality and morbidity in people living with HIV infection. HIV-infected patients with TB disease are at risk of the paradoxical TB-associated immune reconstitution inflammatory syndrome (TB-IRIS) when they commence anti-retroviral therapy. However, the pathophysiology is incompletely understood and specific therapy is lacking. OBJECTIVES: We investigated the hypothesis that invariant Natural Killer T (iNKT) cells contribute to innate immune dysfunction associated with TB-IRIS. METHODS: In a cross-sectional study of 101 HIV-infected and -uninfected South African patients with active TB and controls, iNKT cells were enumerated using α-galactosylceramide-loaded CD1d tetramers and subsequently functionally characterised by flow cytometry. In a second study of 49 HIV-1-infected TB patients commencing anti-retroviral therapy, iNKT cells in TB-IRIS patients with non-IRIS controls were compared longitudinally. MEASUREMENTS AND MAIN RESULTS: Circulating iNKT cells were reduced in HIV-1 infection, most significantly the CD4+ subset, which was inversely associated with HIV-1 viral load. iNKT cells in HIV-associated TB had increased surface CD107a expression, indicating cytotoxic degranulation. Relatively increased iNKT cell frequency in HIV-infected patients with active TB was associated with development of TB-IRIS following anti-retroviral therapy initiation. iNKT cells in TB-IRIS were CD4+CD8- subset deplete and degranulated around the time of TB-IRIS onset. CONCLUSIONS: Reduced iNKT cell CD4+ subsets as a result of HIV-1 infection may skew iNKT cell functionality towards cytotoxicity. Increased CD4- cytotoxic iNKT cells may contribute to immunopathology in TB-IRIS

Relapse and post-discharge body composition of children treated for acute malnutrition using a simplified, combined protocol: A nested cohort from the ComPAS RCT

INTRODUCTION: Severe and moderate acute malnutrition (SAM and MAM) affect more than 50 million children worldwide yet 80% of these children do not access care. The Combined Protocol for Acute Malnutrition Study (ComPAS) trial assessed the effectiveness of a simplified, combined SAM/MAM protocol for children aged 6-59 months and found non-inferior recovery compared to standard care. To further inform policy, this study assessed post-discharge outcomes of children treated with this novel protocol in Kenya. METHODS: Six 'combined' protocol clinics treated SAM and MAM children using an optimised mid-upper arm circumference (MUAC)-based dose of ready-to-use therapeutic food (RUTF). Six 'standard care' clinics treated SAM with weight-based RUTF rations; MAM with ready-to-use supplementary food (RUSF). Four months post-discharge, we assessed anthropometry, recent history of illness, and body composition by bioelectrical impedance analysis. Data was analysed using multivariable linear regression, adjusted for age, sex and allowing for clustering by clinic. RESULTS: We sampled 850 children (median age 18 months, IQR 15-23); 44% of the original trial sample in Kenya. Children treated with the combined protocol had similar anthropometry, fat-free mass, fat mass, skinfold thickness z-scores, and frequency of common illnesses 4 months post-discharge compared the standard protocol. Mean subscapular skinfold z-scores were close to the global norm (standard care: 0.24; combined 0.27). There was no significant difference in odds of relapse between protocols (SAM, 3% vs 3%, OR = 1.0 p = 0.75; MAM, 10% vs 12%, OR = 0.90 p = 0.34). CONCLUSIONS: Despite the lower dosage of RUTF for most SAM children in the combined protocol, their anthropometry and relapse rates at 4 months post-discharge were similar to standard care. MAM children treated with RUTF had similar body composition to those treated with RUSF and neither group exhibited excess adiposity. These results add further evidence that a combined protocol is as effective as standard care with no evidence of adverse effects post-discharge. A simplified, combined approach could treat more children, stretch existing resources further, and contribute to achieving Sustainable Development Goal Two

Health-related quality of life associated with bullying and aggression: a cross-sectional study in English secondary schools.

Associations between adolescent health-related quality of life (HRQoL), bullying, and aggression are not well understood. We used baseline data from a large-cluster randomized school trial to study the relationship between HRQoL, bullying experience, and other demographic factors. Cross-sectional self-reported questionnaires collected pre-randomization from the on-going INCLUSIVE trial. The questionnaires were completed in the classroom. The Gatehouse Bullying Scale measured bullying victimization and the Edinburgh Study of Youth Transitions and Crime school misbehavior subscale (ESYTC) measured aggressive behaviors. HRQoL was assessed using the Child Health Utility 9 Dimensions (CHU-9D) and general quality of life using the Pediatric Quality of Life Inventory (PedsQL). Participants were a cohort of year 7 students (age 11-12 years) from 40 state secondary schools in England. Descriptive statistics for the CHU-9D and PedsQL were calculated using standard methods with tests for differences in median scores by sex assessed using quantile regression. Correlation between HRQoL measures was conducted using Spearman's rank correlation coefficients. Predictors of HRQoL were identified using univariate and multiple regressions. A total of 6667 students filled out the questionnaire. The CHU-9D was correlated with the PedsQL (0.63, p < 0.001). The multivariable regression results suggest that if students were bullied frequently and upset it resulted in a decrement in CHU-9D scores of (-0.108) and fall in PedsQL score of (-16.2). The impact of the antisocial/aggressive behavior on the ESYTC scale resulted in a utility decrement of -0.004 and fall of -.5 on the PedsQL. Adolescents' involvement in bullying and aggression is a strong correlate of HRQoL. These data have important implications for the potential cost-effectiveness of reducing bullying and aggression in schools

Boys are more likely to be undernourished than girls: a systematic review and meta-analysis of sex differences in undernutrition

BACKGROUND: Excess male morbidity and mortality is well recognised in neonatal medicine and infant health. In contrast, within global nutrition, it is commonly assumed that girls are more at risk of experiencing undernutrition. We aimed to explore evidence for any male/female differences in child undernutrition using anthropometric case definitions and the reasons for differences observed. METHODS: We searched: Medline, Embase, Global health, Popline and Cochrane databases with no time limits applied. Eligible studies focused on children aged 0–59 months affected by undernutrition where sex was reported. In the meta-analysis, undernutrition-specific estimates were examined separately for wasting, stunting and underweight using a random-effects model. RESULTS: 74 studies were identified: 44/74 studies were included in the meta-analysis. In 20 which examined wasting, boys had higher odds of being wasted than girls (pooled OR 1.26, 95% CI 1.13 to 1.40). 38 examined stunting: boys had higher odds of stunting than girls (pooled OR 1.29 95% CI 1.22 to 1.37). 23 explored underweight: boys had higher odds of being underweight than girls (pooled OR 1.14, 95% CI 1.02 to 1.26). There was some limited evidence that the female advantage, indicated by a lower risk of stunting and underweight, was weaker in South Asia than other parts of the world. 43/74 (58%) studies discussed possible reasons for boy/girl differences; 10/74 (14%) cited studies with similar findings with no further discussion; 21/74 (28%) had no sex difference discussion. 6/43 studies (14%) postulated biological causes, 21/43 (49%) social causes and 16/43 (37%) to a combination. CONCLUSION: Our review indicates that undernutrition in children under 5 is more likely to affect boys than girls, though the magnitude of these differences varies and is more pronounced in some contexts than others. Future research should further explore reasons for these differences and implications for nutrition policy and practice

Chronic disease outcomes after severe acute malnutrition in Malawian children (ChroSAM): a cohort study

Background Tackling severe acute malnutrition (SAM) is a global health priority. Heightened risk of non-communicable diseases (NCD) in children exposed to SAM at around 2 years of age is plausible in view of previously described consequences of other early nutritional insults. By applying developmental origins of health and disease (DOHaD) theory to this group, we aimed to explore the long-term eff ects of SAM. Methods We followed up 352 Malawian children (median age 9·3 years) who were still alive following SAM inpatient treatment between July 12, 2006, and March 7, 2007, (median age 24 months) and compared them with 217 sibling controls and 184 age-and-sex matched community controls. Our outcomes of interest were anthropometry, body composition, lung function, physical capacity (hand grip, step test, and physical activity), and blood markers of NCD risk. For comparisons of all outcomes, we used multivariable linear regression, adjusted for age, sex, HIV status, and socioeconomic status. We also adjusted for puberty in the body composition regression model. Findings Compared with controls, children who had survived SAM had lower height-for-age Z scores (adjusted diff erence vs community controls 0·4, 95% CI 0·6 to 0·2, p=0·001; adjusted diff erence vs sibling controls 0·2, 0·0 to 0·4, p=0·04), although they showed evidence of catch-up growth. These children also had shorter leg length (adjusted diff erence vs community controls 2·0 cm, 1·0 to 3·0, p<0·0001; adjusted diff erence vs sibling controls 1·4 cm, 0·5 to 2·3, p=0·002), smaller mid-upper arm circumference (adjusted diff erence vs community controls 5·6 mm, 1·9 to 9·4, p=0·001; adjusted diff erence vs sibling controls 5·7 mm, 2·3 to 9·1, p=0·02), calf circumference (adjusted diff erence vs community controls 0·49 cm, 0·1 to 0·9, p=0·01; adjusted diff erence vs sibling controls 0·62 cm, 0·2 to 1·0, p=0·001), and hip circumference (adjusted diff erence vs community controls 1·56 cm, 0·5 to 2·7, p=0·01; adjusted diff erence vs sibling controls 1·83 cm, 0·8 to 2·8, p<0·0001), and less lean mass (adjusted diff erence vs community controls –24·5, –43 to –5·5, p=0·01; adjusted diff erence vs sibling controls –11·5, –29 to –6, p=0·19) than did either sibling or community controls. Survivors of SAM had functional defi cits consisting of weaker hand grip (adjusted diff erence vs community controls –1·7 kg, 95% CI –2·4 to –0·9, p<0·0001; adjusted diff erence vs sibling controls 1·01 kg, 0·3 to 1·7, p=0·005,)) and fewer minutes completed of an exercise test (sibling odds ratio [OR] 1·59, 95% CI 1·0 to 2·5, p=0·04; community OR 1·59, 95% CI 1·0 to 2·5, p=0·05). We did not detect signifi cant diff erences between cases and controls in terms of lung function, lipid profi le, glucose tolerance, glycated haemoglobin A1c, salivary cortisol, sitting height, and head circumference. Interpretation Our results suggest that SAM has long-term adverse eff ects. Survivors show patterns of so-called thrifty growth, which is associated with future cardiovascular and metabolic disease. The evidence of catch-up growth and largely preserved cardiometabolic and pulmonary functions suggest the potential for near-full rehabilitation. Future follow-up should try to establish the eff ects of puberty and later dietary or social transitions on these parameters, as well as explore how best to optimise recovery and quality of life for survivors

Validated tools to identify common mental disorders in the perinatal period: A systematic review of systematic reviews.

BACKGROUND: Uncertainty remains regarding the validity of screening tools to detect common mental disorders (CMDs) during perinatal periods. This umbrella review aims to provide an up-to-date summary of psychometric properties of tools for the identification of perinatal CMDs. METHODS: Reviews were identified via Ovid MEDLINE, PsychINFO, EMBASE, Global Health and Cochrane Database of Systematic Reviews electronic databases with no date or language restriction. Pooled sensitivity and specificity estimates and ranges were extracted and summarised using forest plots. Quality assessment was conducted using Measurement Tool to Assess Systematic Reviews (AMSTAR-2). RESULTS: Of 7,891 papers identified, 31 reviews met inclusion criteria. 76 screening tools were identified; most frequently validated were Edinburgh Postnatal Depression Scale (EPDS) (n = 28 reviews), Beck's Depression Inventory (BDI) (n = 13 reviews) and Patient Health Questionnaire (PHQ) (n = 12 reviews). Forest plots demonstrated a pattern of decreasing sensitivity and increasing specificity with increasing cut-off scores. Sub-group analysis of data extracted from low quality reviews demonstrated wider 95% CIs and overall lower specificity. Validity also varied according to ethnicity, socio-economic background and age. LIMITATIONS: Despite a low Covered Corrected Area (CCA) score the primary studies included within reviews overlapped; therefore we were unable perform meta-analysis. CONCLUSIONS: The evidence suggests that the EPDS, PHQ and BDI are useful across a range of diverse settings but the context of tool application is a key factor determining validity. This review highlights that utilizing screening tools in clinical practice is complex and requires careful consideration of the population, context, and health system it will be used in

Staff experiences of Providing Maternity Services in Rural Southern Tanzania -- A Focus on Equipment, Drug and Supply Issues.

The poor maintenance of equipment and inadequate supplies of drugs and other items contribute to the low quality of maternity services often found in rural settings in low- and middle-income countries, and raise the risk of adverse maternal outcomes through delaying care provision. We aim to describe staff experiences of providing maternal care in rural health facilities in Southern Tanzania, focusing on issues related to equipment, drugs and supplies. Focus group discussions and in-depth interviews were conducted with different staff cadres from all facility levels in order to explore experiences and views of providing maternity care in the context of poorly maintained equipment, and insufficient drugs and other supplies. A facility survey quantified the availability of relevant items. The facility survey, which found many missing or broken items and frequent stock outs, corroborated staff reports of providing care in the context of missing or broken care items. Staff reported increased workloads, reduced morale, difficulties in providing optimal maternity care, and carrying out procedures that carried potential health risks to themselves as a result. Inadequately stocked and equipped facilities compromise the health system's ability to reduce maternal and neonatal mortality and morbidity by affecting staff personally and professionally, which hinders the provision of timely and appropriate interventions. Improving stock control and maintaining equipment could benefit mothers and babies, not only through removing restrictions to the availability of care, but also through improving staff working conditions

A school-based social-marketing intervention to promote sexual health in English secondary schools: the Positive Choices pilot cluster RCT

Background: The UK still has the highest rate of teenage births in western Europe. Teenagers are also the age group most likely to experience unplanned pregnancy, with around half of conceptions in those aged < 18 years ending in abortion. After controlling for prior disadvantage, teenage parenthood is associated with adverse medical and social outcomes for mothers and children, and increases health inequalities. This study evaluates Positive Choices (a new intervention for secondary schools in England) and study methods to assess the value of a Phase III trial. Objectives: To optimise and feasibility-test Positive Choices and then conduct a pilot trial in the south of England assessing whether or not progression to Phase III would be justified in terms of prespecified criteria. Design: Intervention optimisation and feasibility testing; pilot randomised controlled trial. Setting: The south of England: optimisation and feasibility-testing in one secondary school; pilot cluster trial in six other secondary schools (four intervention, two control) varying by local deprivation and educational attainment. Participants: School students in year 8 at baseline, and school staff. Interventions: Schools were randomised (1 : 2) to control or intervention. The intervention comprised staff training, needs survey, school health promotion council, year 9 curriculum, student-led social marketing, parent information and review of school/local sexual health services. Main outcome measures: The prespecified criteria for progression to Phase III concerned intervention fidelity of delivery and acceptability; successful randomisation and school retention; survey response rates; and feasible linkage to routine administrative data on pregnancies. The primary health outcome of births was assessed using routine data on births and abortions, and various self-reported secondary sexual health outcomes. Data sources: The data sources were routine data on births and abortions, baseline and follow-up student surveys, interviews, audio-recordings, observations and logbooks. Results: The intervention was optimised and feasible in the first secondary school, meeting the fidelity targets other than those for curriculum delivery and criteria for progress to the pilot trial. In the pilot trial, randomisation and school retention were successful. Student response rates in the intervention group and control group were 868 (89.4%) and 298 (84.2%), respectively, at baseline, and 863 (89.0%) and 296 (82.0%), respectively, at follow-up. The target of achieving ≥ 70% fidelity of implementation of essential elements in three schools was achieved. Coverage of relationships and sex education topics was much higher in intervention schools than in control schools. The intervention was acceptable to 80% of students. Interviews with staff indicated strong acceptability. Data linkage was feasible, but there were no exact matches for births or abortions in our cohort. Measures performed well. Poor test–retest reliability on some sexual behaviour measures reflected that this was a cohort of developing adolescents. Qualitative research confirmed the appropriateness of the intervention and theory of change, but suggested some refinements. Limitations: The optimisation school underwent repeated changes in leadership, which undermined its participation. Moderator analyses were not conducted as these would be very underpowered. Conclusion: Our findings suggest that this intervention has met prespecified criteria for progression to a Phase III trial. Future work: Declining prevalence of teenage pregnancy suggests that the primary outcome in a full trial could be replaced by a more comprehensive measure of sexual health. Any future Phase III trial should have a longer lead-in from randomisation to intervention commencement